Evolutionary plasticity of SH3 domain binding by Nef proteins of the HIV-1/SIVcpz lentiviral lineage
Zhao, Z., Fagerlund, R., Tossavainen, H., Hopfensperger, K., Lotke, R., Srinivasachar, B. S., Kirchhoff, F., Permi, P., Sato, K., Sauter, D., & Saksela, K. (2021). Evolutionary plasticity of SH3 domain binding by Nef proteins of the HIV-1/SIVcpz lentiviral lineage. PLoS Pathogens, 17(11), Article e1009728. https://doi.org/10.1371/journal.ppat.1009728
Published inPLoS Pathogens
DisciplineNanoscience CenterNanoscience Center
© 2021 the Authors
The accessory protein Nef of human and simian immunodeficiency viruses (HIV and SIV) is an important pathogenicity factor known to interact with cellular protein kinases and other signaling proteins. A canonical SH3 domain binding motif in Nef is required for most of these interactions. For example, HIV-1 Nef activates the tyrosine kinase Hck by tightly binding to its SH3 domain. An archetypal contact between a negatively charged SH3 residue and a highly conserved arginine in Nef (Arg77) plays a key role here. Combining structural analyses with functional assays, we here show that Nef proteins have also developed a distinct structural strategy—termed the "R-clamp”—that favors the formation of this salt bridge via buttressing Arg77. Comparison of evolutionarily diverse Nef proteins revealed that several distinct R-clamps have evolved that are functionally equivalent but differ in the side chain compositions of Nef residues 83 and 120. Whereas a similar R-clamp design is shared by Nef proteins of HIV-1 groups M, O, and P, as well as SIVgor, the Nef proteins of SIV from the Eastern chimpanzee subspecies (SIVcpzP.t.s.) exclusively utilize another type of R-clamp. By contrast, SIV of Central chimpanzees (SIVcpzP.t.t.) and HIV-1 group N strains show more heterogenous R-clamp design principles, including a non-functional evolutionary intermediate of the aforementioned two classes. These data add to our understanding of the structural basis of SH3 binding and kinase deregulation by Nef, and provide an interesting example of primate lentiviral protein evolution. ...
PublisherPublic Library of Science
ISSN Search the Publication Forum1553-7366
Publication in research information system
MetadataShow full item record
Related funder(s)Academy of Finland; Jane and Aatos Erkko Foundation
Funding program(s)Academy Project, AoF; Foundation
Additional information about fundingKS was funded by the Helsinki University Central Hospital Research Council grant TYH2017248 and by the Jane and Aatos Erkko Foundation (JAES2016). PP was supported by grants from the Academy of Finland (323435) and Jane and Aatos Erkko Foundation (JAES2019). DS was supported by the Heisenberg Program (SA 2676/3-1) and the Priority Program SPP1923 (SA2676/1-2) of the German Research Foundation (DFG). ...
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